Macrophage modulation in activation process induced immune thrombocytopenia

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Mahdaleny Mahdaleny
Arleni Bustami
Febriana Catur Iswanti


The immune system operates like an orchestra that harmoniously maintains the homeostasis balance while protecting from external or internal pathogens attack. Inflammation is one of the key critical immune defenses to eradicate pathogens and encourage tissue repair and recovery by activating the host’s immune and non-immune cells. As a part of the immune response during inflammation, blood platelets serve various functions; however, their activation and involvement in inflammation can also contribute to pathological conditions, such as thrombosis, which results in myocardial infarction, stroke, and venous thromboembolism. Activated platelets can mobilize and release intracellular granules (alpha and dense granules), which include secondary mediators like chemokine PF4/CXCL4. In contrast to most other chemokines, PF4 participates in several long-term regulatory processes, such as cell differentiation, survival, and proliferation. However, recent findings suggest that PF4 is also responsible for modulating macrophage polarization, which can substantially impact the development of induced immune thrombotic thrombocytopenia. This review aims to explain how PF4 induced vascular problems by modulation of macrophage development during immunological thrombocytopenia. A literature search using the keywords PF4, CXCL4, macrophage M4, platelet macrophage M4, and induced immune thrombocytopenia was done using the following databases: Google Scholar, ProQuest, ScienceDirect, and Scopus for articles published from 2000 to 2023. The literature study was done to find the connection between platelet activation, macrophage modulation, and vascular problems such as atherosclerosis and thromboembolism in induced immune thrombotic thrombocytopenia. Several recent studies on PF4, macrophage modulation, and vaccine-induced thrombotic thrombocytopenia were carefully reviewed. This review concludes that macrophage polarization modulation is promising in managing vascular problems in patients with induced immune thrombotic thrombocytopenia.

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How to Cite
Mahdaleny, M., Bustami, A. ., & Iswanti, F. C. . (2024). Macrophage modulation in activation process induced immune thrombocytopenia. Universa Medicina, 43(1), 76–87.
Review Article


Sansbury BE, Spite M. Resolution of acute inflammation and the role of resolvins in immunity, thrombosis, and vascular biology. Circ Res 2016; 119:113-30. doi: 10.1161/ CIRCRESAHA.116. 307308.

Nakayama Y, Fujiu K, Yuki R, et al. A long noncoding RNA regulates inflammation resolution by mouse macrophages through fatty acid oxidation activation. Proc Natl Acad Sci U S A 2020;117:14365-75. doi: 10.1073/pnas. 2005924117.

Oishi Y, Manabe I. Macrophages in inflammation, repair and regeneration. Int Immunol 2018;30:511-28. doi: 10.1093/intimm/ dxy054.

Watanabe S, Alexander M, Misharin AV, Budinger GRS. The role of macrophages in the resolution of inflammation. J Clin Invest 2019; 129:2619-28. doi: 10.1172/JCI124615.

Alfaro S, Acuña V, Ceriani R, et al. Involvement of inflammation and its resolution in disease and therapeutics. Int J Mol Sci 2022;23:10719. doi: 10.3390/ijms231810719.

Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM. Resolution of inflammation: what controls its onset? Front Immunol 2016;7:160. doi: 10.3389/fimmu.2016.00160.

Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013;496:445-55. doi: 10.1038/nature 12034.

Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med 2019;25:1822-32. doi: 10.1038


Badimon L, Padró T, Vilahur G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care 2012; 1:60-74. doi: 10.1177/2048872612441582

Yan C, Wu H, Fang X, He J, Zhu F. Platelet, a key regulator of innate and adaptive immunity. Front Med 2023;10:1074878. doi: 10.3389/fmed.2023. 1074878.

Chaudhary PK, Kim S, Kim, S. An insight into recent advances on platelet function in health and disease. Int J Mol Sci 2022; 23: 6022. DOI:

Austermann J, Roth J, Barczyk-Kahlert K. The good and the bad: monocytes’ and macrophages’ diverse functions in inflammation. Cells 2022;11:1979. doi: 10.3390/cells11121979.

Chinetti-Gbaguidi G, Colin S, Staels B. Macrophage subsets in atherosclerosis. Nat Rev Cardiol 2015;12:10-7. doi: 10.1038/nrcardio. 2014.173.

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 Macrophages and the Th1/Th2

paradigm. J Immunol 2000;164:6166-73. doi: 10.4049/jimmunol.164.12.6166.

Gleissner CA. Macrophage phenotype modulation by CXCL4 in atherosclerosis. Front Physiol. 2012;3:1. doi: 10.3389/fphys.2012. 00001

Krauel K, Weber C, Brandt S, et al. Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes. Blood 2012; 120:3345-52. doi: 10.1182/blood-2012-06- 434985.

Arman M, Krauel K, Tilley DO, et al. Amplification of bacteria-induced platelet activation is triggered by Fc RIIA, integrin IIb 3, and platelet factor 4. Blood 2014;123:3166-74. doi: 10.1182/blood-2013-11-540526.

Cai Z, Greene MI, Zhu Z, Zhang H. Structural features and PF4 Functions that occur in heparin- induced thrombocytopenia (HIT) complicated by COVID-19. Antibodies (Basel) 2020;9:52. doi: 10.3390/antib9040052.

Franchini M, Liumbruno GM, Pezzo M. COVID‐

vaccine‐associated immune thrombosis and thrombocytopenia (VITT): diagnostic and therapeutic recommendations for a new syndrome. Eur J Haematol 2021;107:173-80. doi: 10.1111/ejh. 13665.

Mcgonagle D, Marco G De, Bridgewood C. Mechanisms of immunothrombosis in vaccine- induced thrombotic thrombocytopenia (VITT) compared to natural SARS-CoV-2 infection. Autoimmun 2021;121:102662. doi: 10.1016/j.jaut.2021.102662.

Hottz ED, Bozza FA, Bozza PT. Platelets in Immune Response to Virus and Immunopathology of Viral Infections. Front Med (Lausanne) 2018;5:121. doi: 10.3389/fmed.2018. 00121.

Giles JB, Miller EC, Steiner HE, Karnes JH. Elucidation of cellular contributions to heparin- induced thrombocytopenia using omic approaches. Front Pharmacol 2022;12:812830. doi: 10.3389/ fphar.2021.812830.

Wolff M, Handtke S, Palankar R, et al. Activated platelets kill Staphylococcus aureus, but not Streptococcus pneumoniae—the role of FcγRIIa and platelet factor 4/heparin antibodies. J Thromb Haemost 2020;18:1459-68. doi: 10.1111/jth. 14814.

Simon AY, Sutherland MR, Pryzdial ELG. Dengue virus binding and replication by platelets. Blood 2015;126:378-85. doi: 10.1182/blood- 2014-09-598029.

Willemsen L, Winther MP. Macrophage subsets in atherosclerosis as defined by single‐cell technologies. J Pathol 2020;250:705-14. doi: 10.1002/path.5392.

Fullerton JN, Gilroy DW. Resolution of inflammation: a new therapeutic frontier. Nat Rev

Drug Discov 2016;15:551–67. doi: 10.1038/nrd. 2016.39.

Doran AC, Yurdagul A, Tabas I. Efferocytosis in health and disease. Nat Rev Immunol 2020;20:254–67. doi: 10.1038/s41577-019-0240- 6.

Hine AM, Loke P. Intestinal macrophages in resolving inflammation. J Immunol 2019

;203:593–9. doi: 10.4049/jimmunol.1900345.

Prame Kumar K, Nicholls AJ, Wong CHY. Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res 2018; 371:551–65. doi: 10.1007/s00441-017-2753-2.

Ross EA, Devitt A, Johnson JR. Macrophages: the good, the bad, and the gluttony. Front Immunol 2021;12:1–22. doi: 10.3389/fimmu.2021/708186.

Allard B, Panariti A, Martin JG. Alveolar macrophages in the resolution of inflammation, tissue repair, and tolerance to infection. Front Immunol 2018;9:1777. doi: 10.3389/fimmu.2018. 01777.

Wu J, Zhang L, Shi J, et al. Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury. EbioMedicine 2020;58: 102920. doi: 10.1016/j. ebiom.2020.102920.

Lafuse WP, Wozniak DJ, Rajaram MVS. Role of cardiac macrophages on cardiac inflammation, fibrosis and tissue repair. Cells 2020;10:51. doi: 103390/cells10010051.

Chen B, Brickshawana A, Frangogiannis NG. The functional heterogeneity of resident Cardiac macrophages in myocardial injury: CCR2 + cells promote inflammation, whereas CCR2 − cells protect. Circ Res 2019;124:183–5. doi: 10.1161/ CIRCRESAHA.118.314357.

Lima MTNS, Howsam M, Anton PM, Delayre‐ orthez C, Tessier FJ. Effect of advanced glycation end‐products and excessive calorie intake on diet‐ induced chronic low‐grade inflammation biomarkers in murine models. Nutrients 2021;13: 3091. doi: 10.3390/nu13093091.

Zhou WBS, Meng JW, Zhang J. Does low grade systemic inflammation have a role in chronic pain? Front Mol Neurosci 2021;14:1–10. doi: 10.3389/ fnmol.2021.785214.

Schett G, Neurath MF. Resolution of chronic inflammatory disease: universal and tissue- specific concepts. Nat Commun 2018;9:3261. doi: 10.1038/ s41467-018-05800-6.

Kulkarni OP, Lichtnekert J, Anders HJ, Mulay SR. The immune system in tissue environments regaining homeostasis after injury: is “inflammation” always inflammation? Mediators Inflamm 2016;2016:2856213. doi: 10.1155/2016/ 2856213.

Chen Y, Zhong H, Zhao Y, Luo X, Gao W. Role of platelet biomarkers in inflammatory response.

Biomark Res 2020;8:28. doi: 10.1186/s40364- 020-00207-2.

Scherlinger M, Richez C, Tsokos GC, Boilard E, Blanco P. The role of platelets in immune- mediated inflammatory diseases. Nat Rev Immunol 2023;23:495-510. doi: 10.1038/ s41577-023-00834-4.

Affandi AJ, Carvalheiro T, Ottria A, et al. CXCL4 drives fibrosis by promoting several key cellular and molecular processes. Cell Rep 2022;38: 110189. doi: 10.1016/j.celrep.2021.110189.

Rossaint J, Thomas K, Mersmann S, et al. Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education. J Exp Med 2021;218: e20201353. doi: 10.1084/jem.20201353.

Zhang Z, Ni C, Chen W, et al. Expression of CXCR4 and breast cancer prognosis: a systematic review and meta-analysis. BMC Cancer 2014;14: 1–8. doi: 10.1186/1471-2407-14-49.

Gleitz HLFE, Dugourd ALJF, Leimkühler NB, et al. Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN. Blood 2020;136:2051– 64. doi: 10.1182/blood.2019004095.

Margraf A, Zarbock A. Platelets in inflammation and resolution. J Immunol 2019;203:2357–67. doi: 10.4049/jimmunol.1900899.

Silva-Cardoso SC, Tao W, Angiolilli C, et al. CXCL4 Links inflammation and fibrosis by reprogramming monocyte-derived dendritic cells in vitro. Front Immunol 2020;11:2149. doi: 10.3389/fimmu.2020.02149.

Ludwig N, Hilger A, Zarbock A, Rossaint J. Platelets at the crossroads of pro-inflammatory and resolution pathways during inflammation. Cells 2022;11:1957. doi: 10.3390/cells11121957.

Johnston I, Sarkar A, Hayes V, et al. Recognition of PF4-VWF complexes by heparin-induced thrombocytopenia antibodies contributes to thrombus propagation. Blood 2020;135:1270–80. doi: 10.1182/blood.2018881607.

Iannacone M. Platelet-mediated modulation of adaptive immunity. Semin Immunol 2016;28: 555–60. doi: 10.1016/j.smim.2016.10.008.

Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood 2014;123: 2759–67. doi: 10.1182/blood-2013-11-462432.

Rolfes V, Ribeiro LS, Hawwari I, et al. Platelets fuel the inflammasome activation of innate immune cells. Cell Rep 2020;31107615. doi: 10.1016/j.celrep.2020.107615.

Gros A, Ollivier V, Ho-Tin-Noé B. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol 2015;5:678. doi: 10.3389/fimmu.2014.00678.

Xie T, Wang Y, Deng N, et al. Single-cell deconvolution of fibroblast heterogeneity in

mouse pulmonary fibrosis. Cell Rep 2018;22: 3625–40. doi: 10.1016/j.celrep.2018.03.010.

Erbel C, Wolf A, Lasitschka F, et al. Prevalence of M4 macrophages within human coronary atherosclerotic plaques is associated with features of plaque instability. Int J Cardiol 2015;186:219- 25. doi: 10.1016/j.ijcard.2015.03.151.

Marques L. Iron homeostasis in immune mononuclear cells: a potential role in atherogenesis.[thesis]. Lisboa: Universidade de Lisboa Portugal; 2015. doi: 10.13410/RG.2.2. 24210.40643.

Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013;13:34-45. doi: 10.1038/ nri3345.

Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015;126:582–8. doi: 10.1182/ blood-2014-08-531582.

Scheuerer B, Ernst M, Dürrbaum-Landmann I, et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000;95:1158–66. PMID: 10666185.

Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol 2020; 40:20–33. doi: 10.1161/ATVBAHA.119.312802.

de Sousa JR, Lucena Neto FD, Sotto MN, Quaresma JAS. Immunohistochemical characterization of the M4 macrophage population in leprosy skin lesions. BMC Infect Dis 2018;18:576. doi: 10.1186/s12879-018-3478- x.

Inui M, Tazawa K, Kishi Y, Takai T. Platelets convert peripheral blood circulating monocytes to regulatory cells via immunoglobulin G and activating-type Fcγ receptors. BMC Immunol 2015;16:20. doi: 10.1186/s12865-015-0086-z.

Roberts CA, Durham LE, Fleskens V, Evans HG, Taams LS. TNF blockade maintains an IL-10+ phenotype in human effector CD4+ and CD8+ T cells. Front Immunol 2017;15:8:157. doi: 10.3389/fimmu.2017.00157.

Joshi L, Ponnana M, Sivangala R, et al. Evaluation of TNF-α, il-10 and il-6 cytokine production and their correlation with genotype variants amongst tuberculosis patients and their household contacts. PLoS One 2015;10:1–15. doi: 10.1371/journal. pone.0137727.

Kara M, Beser OF, Konukoglu D, et al. The utility of TNF-α, IL-6 and IL-10 in the diagnosis and/or follow-up food allergy. Allergol Immunopathol (Madr) 2020;48:48–55. doi: 10.1016/j.aller. 2019. 04.011.

Papoutsopoulou S, Pollock L, Williams JM, et al. Interleukin-10 deficiency impacts on TNF- induced NFκB regulated responses in vivo.

Biology (Basel) 2022;11:1377. doi: 10.3390/ biology11101377.

Domschke G, Gleissner CA. Cytokine CXCL4- induced macrophages in human atherosclerosis. Cytokine 2019;122:154141. doi: 10.1016/j.cyto. 2017.08.021.

Fox JM, Kausar F, Day A, et al. CXCL4 / Platelet Factor 4 is an agonist of CCR1 and drives human monocyte migration. Sci Rep 2018;8:9466. doi: 10.1038/s41598-018-27710-9.

Kang I, Chang MY, Wight TN, Frevert CW. Proteoglycans as immunomodulators of the innate immune response to lung infection. J Histochem Cytochem 2018;66:241–59. doi: 10.1369/ 0022155417751880.

Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FW, Jansen AG. Emerging concepts in immune thrombocytopenia. Front Immunol 2018; 9:880. doi: 10.3389/fimmu.2018.00880.

Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev 2017;16: 620-32. doi: 10.1016/j.autrev.2017.04.012.

Grodzielski M, Goette NP, Glembotsky AC, et al. Multiple concomitant mechanisms contribute to low platelet count in patients with immune thrombocytopenia. Sci Rep 2019;9:2208. doi: 10.1038/s41598-018-38086-1.

Audia S, Mahévas M, Nivet M, Ouandji S, Bonnotte B. Immune thrombocytopenia: recent advances in pathogenesis and treatments. Hemasphere 2021;5:e574. doi: 10.1097/HS9. 0000000000000574.

Zufferey A, Kapur R, Semple JW. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J Clin Med 2017;6:16. doi: 10.3390/jcm6020016.

Kelton JG, Arnold DM, Nazy I. Lessons from vaccine-induced immune thrombotic thrombocytopenia. Nat Rev Immunol 2021;21: 753-5. doi: 10.1038/s41577-021-00642-8.

Greinacher A, Schönborn L, Siegerist F, et al. Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). Semin Hematol 2022;59:97-107. doi: 10.1053/j. seminhematol.2022.02.004.

Cai Z, Greene MI, Zhu Z, Zhang H. Structural features and PF4 functions that occur in heparin- induced thrombocytopenia (HIT) complicated by

COVID-19. Antibodies 2020;9:52. doi: 10.3390/ antib9040052.

Greinacher A, Warkentin TE. Platelet factor 4 triggers thrombo‐inflammation by bridging innate and adaptive immunity. Int J Lab Hematol 2023; 45(Suppl. 2):11-22. doi: 10.1111/ijlh.14075.

Shao X, Xu P, Ji L, et al. Low‐dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter. Clin Transl Med 2023;13:e1344. doi: 10.1002/ ctm2.1344.

Li D, Liu Q, Sun W, et al. 1,3,6,7-Tetrahydroxy- 8-prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages: A xanthone attenuates adipose tissue inflammation. Br J Pharmacol 2018;175:1590–606. doi: 10.1111/ bph. 14162.

Xu J, Liu Y, Zhao Z, Zhao L, Wang D, Liu Q. The role of traditional Chinese medicine in the treatment of atherosclerosis through the regulation of macrophage activity. Biomed Pharmacother 2019; 118:109375. doi: 10.1016/j.biopha.2019.109375.

Rolla R, Puricelli C, Bertoni A, et al. Platelets: ‘multiple choice’ effectors in the immune response and their implication in COVID-19 thromboinflammatory process. Int J Lab Hematol 2021;43:895–906. doi: 10.1111/ijlh.13516.

Jenne CN, Urrutia R, Kubes P. Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 2013;35:254–61. doi: 10.1111/ijlh. 12084.

Ali RA, Wuescher LM, Worth RG. Platelets: essential components of the immune system. Curr Trends Immunol 2015;16:65–78.

Ribeiro LS, Branco LM, Franklin BS. Regulation of innate immune responses by platelets. Front Immunol 201;10:1320. doi: 10.3389/fimmu.2019. 01320.

Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res 2013;112:1506–19. doi: 10.1161/CIRCRESAHA.113.300512.

Becker RC, Sexton T, Smyth SS. Translational implications of platelets as vascular first responders. Circ Res 2018;122:506-22. doi: 10.1161/CIRCRESAHA.117.310939.